The candidate, Dr. John W. Huffman, is a professor of chemistry at Clemson University whose research interests are the design and synthesis of new cannabinoid receptor ligands. At the present time Dr. Huffman devotes approximately 50% of his time to research; the Senior Scientist award will increase this to 80%. The candidate was trained as a synthetic organic chemist with little formal education in biochemistry and none in pharmacology or molecular modeling. His short term career objectives are to gain some expertise in these areas through increased interactions with his collaborators and by auditing courses in biochemistry. Dr. Huffman's long term career goals are to use this increased knowledge to improve his ability to design effective cannabinoid receptor ligands. Training in these disciplines will also improve his proficiency in mentoring graduate students and postdoctorals who will seek careers in the pharmaceutical industry or academe. A short and long term career goal is to assist Clemson University in developing a program in training in the responsible conduct of research. A major objective of our synthetic program continues to be the exploration of structural similarities and dissimilarities among various classes of cannabinoids and the development of agonists and antagonists with selective pharmacological profiles. These goals will be reached through the synthesis of new potential agonists and antagonists in Dr. Huffman's laboratories. Pharmacological evaluation of the ligands will be carried out through a collaborative agreement with Dr. B. R. Martin, Virginia Commonwealth University. Alternative pharmacological investigations will be performed by Dr. R. G. Pertwee, University of Aberdeen (UK). Among the new ligands to be synthesized are additional indole and pyrrole based potential agonists and antagonists to obtain additional ligands which show receptor selectivity, selective agonist properties and/or provide additional insight into the manner in which cannabimimetic indoles and pyrroles interact with each receptor. Rigid indole and indene analogues will also be prepared and their pharmacology evaluated. Additional 1-deoxycannabinoids will be prepared. These compounds are designed to be highly selective agonists for the CB2 receptor, which will have little affinity for the CB1 receptor. A number of new classical cannabinoids will be synthesized, including additional 1',2'-dimethylheptyl-delta8-tetrahydrocannabinol analogues and the six geminally disubstituted dimethylheptyl-delta8-tetrahydrocannabinols.